Optimizing release of dry medicament powder

ABSTRACT

A method based on an Air-razor tool is disclosed thereby providing improved release and dispersal into air of a dose of medication powder. When air is sucked through a suction tube, particles of a powder dose, made available to the suction tube, are gradually released and dispersed into a stream of air entering the suction tube. The gradual release and dispersal is produced by a relative motion introduced between the suction tube and the dose. The high velocity air going into the suction tube inlet provides plenty of shearing stress and inertia energy as the flowing air hits the leading point of the dose. This powder Air-razor method, created by the shearing stress and inertia of the air stream, is so powerful that the particles of the powder adjacent to the inlet of the moving suction tube are released and subsequently entrained in the air stream going through the suction tube.

TECHNICAL FIELD

The present invention relates to a method for releasing and dispersinginto a stream of air a metered dose of dry medication powder from asubstrate member, and more specifically to a method of optimizingrelease of a metered dry powder dose from a substrate member andentraining the powder into an inhalation airflow.

BACKGROUND

Different types of inhalers are available on the market today, such asmetered dose inhalers (MDIs), nebulizers and dry powder inhalers (DPIs).MDIs use medicaments in liquid form and may use a pressurized drive gasto release a dose. Nebulizers are fairly big, non-portable devices. Drypowder inhalers have become more and more accepted in the medicalservice, because they deliver an effective dose in a single inhalation,they are reliable, often quite small in size and easy to operate for auser. Two types are common, multi-dose dry powder inhalers and singledose dry powder inhalers. Multi-dose devices have the advantage that aquantity of medicament powder, enough for a large number of doses, isstored inside the inhaler and a dose is metered from the store shortlybefore it is supposed to be inhaled. Single dose inhalers either requirereloading after each administration or they may be loaded with a limitednumber of individually packaged doses, where each package is openedshortly before inhalation of the enclosed dose is supposed to takeplace. Single dose dry powder inhalers capable of pulmonary delivery ofpre-metered, systemically acting and sensitive medicaments areattracting much interest today, especially when such devices provideprotection for formulations against varying ambient conditions, inparticular humidity.

The active substance in dry powder form, suitable for inhalation needsto be finely divided so that the majority by mass of particles in thepowder is between 1 and 5 μm in aerodynamic diameter (AD). Powderparticles larger than 5 μm in AD tend not to deposit in the lung wheninhaled but to stick in the mouth and upper airways, where they aremedicinally wasted and may even cause adverse side effects. However,finely divided powders, suitable for inhalation, are rarely free flowingbut tend to stick to all surfaces they come in contact with and thesmall particles tend to aggregate into lumps. This is due to van derWaal forces generally being stronger than the force of gravity acting onsmall particles having diameters of 10 μm or less. There are severalmicronization technologies known in the art. Two major categoriesdominate in prior art: breaking of large particles using milling processsuch as jet milling, pearl-ball milling or high-pressure homogenizationand the production of small particles using controlled productionprocesses such as spray drying, lyophilization, precipitation fromsupercritical fluid and controlled crystallization. The former categoryproduces predominantly crystalline, homogenous particles, the lattermore amorphous, ‘light’, porous particles. See e.g. “Micron-Size DrugParticles: Common and Novel Micronization techniques” by Lee Siang Hua.In this document the term ‘finely divided powder’ refers to inhalableparticles in general and does not limit or preclude any method ofproducing such particles.

Because most active drugs are very potent, only a fraction of amilligram is needed in a dose in many cases. Before filling it isgenerally necessary to dilute the drug using a suitable, physiologicallyinert excipient, e.g. lactose. Today, nominal inhalation doses of lessthan I mg and even less than 0.5 mg are not unusual. Such small dosesare very difficult to meter and fill using prior art methods. See forinstance the publication U.S. Pat. No. 5,865,012 and WO 03/026965 A1.The problem of bad flowability in the powder is often addressed byselecting an excipient as carrier, which comprises bigger particles thanthe drug, i.e. aerodynamic particle diameters for the excipient largerthan 10 μm. A common practice in the pharmaceutical industry is todilute the active substance further, in order to increase the nominaldose mass to a level, which the filling method of choice can handle.Typically, volumetric doses in prior art have masses in a range from 5to 50 mg.

Turning to the drug formulation, there are a number of well-knowntechniques, as mentioned above, to obtain an appropriate primaryparticle size distribution to ensure correct lung deposition for a highpercentage of the dose. There are also a number of well-known techniquesfor modifying the forces between the particles and thereby obtaining apowder with e.g. small adhesive forces. Such methods includemodification of the shape and surface properties of the particles, e.g.porous particles and controlled forming of powder pellets, as well asaddition of an inert carrier with a larger average particle size (socalled ordered mixture). Naturally, independent of which method ofmaking the formulation is preferred, a narrow particle size distributionproviding a high fine particle fraction (FPF) of the activepharmaceutical ingredient (API) formulation is an advantage, where themass median aerodynamic diameter (MMAD) preferably is in a range between0.5 and 3 μm, if pulmonary delivery is the objective.

Novel drugs, both for local and systemic delivery, often includebiological macromolecules, which put completely new demands on theformulation. In our publication WO 02/11803 (U.S. Pat. No. 6,696,090) amethod and a process is disclosed of preparing a so calledelectro-powder, suitable for forming doses by an electro-dynamic method.The disclosure stresses the importance of controlling the electricalproperties of a medication powder and points to the problem of moisturein the powder and the need of low relative humidity in the atmosphereduring dose forming.

A successful delivery to the deep lung also assumes that the inspirationtakes place in a calm manner to decrease air speed in the airways andthereby reduce deposition by impaction in the upper respiratory tracts.The advantages of using the inhalation power of the user to fullpotential in a prolonged, continuous dose delivery interval within theinhalation cycle is disclosed in our U.S. Pat. No. 6,622,723 (WO01/34233 A1), which is incorporated herein by reference. The patentpresents several devices for efficient distribution of pharmaceuticalcompositions in fine powder form in the inspiration air, without needingother sources of energy than the power of the airstream resulting fromthe user's inhalation.

A method and device, for aerosolizing and, if necessary, de-aggregatingpowders for inhalation, based on a relative motion between a powder doseand a suction nozzle are disclosed in our U.S. Pat. Nos. 6,892,727 and6,840,239, which are incorporated herein by reference. The disclosuresteach that adopting an Air-razor method and device, when applied in adry powder inhaler device, advantageously aerosolize dry, fine powderdoses, but give only little information about what formulations may beused. The preferred embodiments of the disclosures were based primarilyon an electro-dynamic method of producing pre-metered doses of finelydivided APIs with or without excipients present in a mixture. Most ofthe doses were porous, which is easily obtained in the electro-dynamicforming method, and needed to be extended, thereby occupying a muchlarger surface area of the available substrate member than would benecessary for a similar dose metered and filled using conventionalfilling methods, such as volumetric filling. Having knowledge of theabove mentioned documents, it would not be obvious to a person ofordinary skill in the art to assume that the Air-razor method couldsuccessfully be applied to any dry powder formulation. Furthermore, itwould not be obvious to a skilled person to apply the Air-razor methodto new formulations and fill doses thereof using standard industryfilling methods.

The present invention is directed to improving the Air-razor method andto disclose some preferred embodiments of a device performing theimproved method.

SUMMARY

A method for releasing and dispersing into flowing air a dose of drymedication powder and more specifically a method of optimizing emissionof the dose from a dry powder inhaler comprising an Air-razor device forreleasing powder. In contrast to prior art, the present invention doesnot require other sources of energy besides the power of the inhalationeffort by the receiver to produce a very high degree of dose releasefrom a substrate member and efficient dispersal of the dose intostreaming air.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention, together with further objects and advantages thereof, maybest be understood by referring to the following detailed descriptiontaken together with the accompanying drawings, in which:

FIG. 1 illustrates the different forces acting on a stationary particlesituated in a stream of air;

FIG. 2 illustrates in a timing diagram a typical inhalation cycleshowing pressure and flow;

FIG. 3 illustrates test data from in-vitro testing of an optimizedAir-razor device in an adapted DPI;

FIG. 4 illustrates in a stylized drawing a substrate member and aconcentrated dose thereon;

FIG. 5 illustrates in a stylized drawing a substrate member and aspread-out dose thereon;

FIG. 6 illustrates in a stylized drawing a substrate member and a dosein a spot thereon;

FIG. 7 illustrates in perspective (FIG. 1 a), top (FIG. 1 b) and side(FIG. 1 c) views a particular embodiment of a sealed dose containerfilled with a dose of a medicament and a dose of an excipient;

FIG. 8 illustrates a sealed dose container after agitation filled with adose of a medicament consisting of two deposits and a dose of anexcipient consisting of three deposits where the doses have becomepartly mixed;

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention makes the Air-razor method and device applicableto all types of dry powder formulations of inhalable medication powders.Furthermore, standard filling methods and equipment may be used to meterand fill doses of a chosen formulation. The doses can then be applied toan adapted DPI, comprising an Air-razor device optimized for theformulation, where the emitted doses and the fine particle doses (FPD)delivered by the DPI present excellent results in terms of quantity andquality compared to the original, metered doses of said chosenformulation. Naturally, the emitted dose and the FPD cannot exceed whatis in the metered dose before it is sucked up.

As used herein, the term “Air-razor method” refers to a method where thedifference in external forces acting on two particles in a doseovercomes the adhesion and friction forces holding them together. Asused herein, the term “Air-razor device” refers to a device capable ofproviding, via energy imput by a user via inhalation and movement of adose and/or suction tube, a difference in external forces acting on twoparticles that overcomes the adhesion and friction forces holding themtogether. The external forces referred to ensue from the induced flow ofair developing from a suction effort provided by a user and applied toan adapted DPI comprising an Air-razor device.

The present invention discloses an improved Air-razor method ofreleasing a dose of dry medication powder from a substrate member anddispersing the powder particles into an airstream. The invention teachesthat a dose of dry medication powder may be emitted from a dry powderinhaler comprising an Air-razor device, whereby the dose is delivered toa receiver with an extremely high fine particle dose (FPD) of theemitted dose coming very close to the original fine particle fraction(FPF) of the original powder formulation. In a further aspect, theinvention teaches that the Air-razor method may be optimized and themethod implemented in an Air-razor device design, which offers very lowretention of particles both on the substrate member, includingassociated surfaces, and downstream flow channels, which are in contactwith the powder before and during dose emission.

Interestingly enough, we have been able to optimize the Air-razor methodand device and to implement this in an adapted DPI. Test data showexcellent results in emitted dose relative metered dose and in deliveredfine particle dose relative emitted dose, when the Air-razor isoptimized for a particular powder formulation. See FIG. 3, whichillustrates in-vitro testing of an optimized Air-razor method and anAir-razor device applied in a dry powder inhaler device. The total doseis 1 mg of a pure, micronized API. The total dose in the example isequivalent to a metered dose. The tests show that the FPD<3.5 μm of thedelivered dose (equivalent to emitted dose) is more than 70% for 4 kPasuction pressure and more than 65% for 2 kPa suction pressure. Theoptimized Air-razor is quite insensitive to variations in the timeperiod for a relative motion of substrate member and a suction tube, asillustrated (‘standard inhalation time’ signifies motion inapproximately 0.7 s, ‘fast inhalation time’ signifies about 0.3 s forthe motion and ‘slow inhalation time’ signifies about 1.2 s for therelative motion to be completed). The Air-razor is also insensitive tothe orientation of the inhaler, i.e. the Air-razor itself. Furthermore,particle retention on the substrate member acting as carrier of the doseis also minimized by the optimization, which may optionally also includeminimizing retention on the inside walls of the downstream air channels.Total retention is normally less than 10% as illustrated in FIG. 3. Bylimiting the suction power driving the Air-razor effect to be within thepreferred range from 2 to 4 kPa, we have still been able to adjust theAir-razor for any type of dry powder formulation used in thepharmaceutical industry. Examples of suitable powder formulationsinclude those produced by jet-milling, spray-drying and super-criticalcrystallization. Powders of micronized, solid particles or powders ofporous particles of low density can be advantageously released andaerosolized by the Air-razor method.

It has been possible to improve the Air-razor method to worksatisfactorily regardless of what metering and filling method ispreferred, including gravimetric, volumetric, electrostatic andelectro-dynamic methods and combinations thereof. The most importantparameters to control are suction tube inlet aperture size, which shallpreferably have a slightly larger diameter at right angles to thedirection of the motion than the width of the dose deposit(s), a gapbetween the inlet aperture and the substrate member of preferably notmore than two millimetres and a speed of the relative motion betweensubstrate member and suction tube, or vice versa, preferably notexceeding 100 mm/s. Preferably, time for the relative motion, within thetime for a suction effort, e.g. an inhalation cycle, is in a range ofapproximately 0.2 s to 2 s from beginning to end for optimal results.

An important element of the Air-razor method is a relative motionbetween a suction tube, comprising an inlet nozzle, and a powder dose.In this document the term “relative motion” refers to the non-airbornepowder, which constitutes a dose that is gradually moved, relativelyspeaking, by the motion into close proximity to the inlet aperture ofsaid suction tube. Thus, it is irrelevant for the efficacy of theAir-razor method how the relative motion is arranged, i.e. if a suctiontube is brought in motion or if it is the dose or, indeed, a combinationof motions. A motion of the dose is preferably brought about by moving asubstrate onto which the dose is deposited, but other means e.g.vibrating or shock devices may also be used. An airstream, induced bysuction, going at speed into the suction tube inlet aperture bringsabout the release of individual powder particles and dispersal ofparticles into the airstream, optionally also providing de-aggregationof aggregated particles. Said term does not refer to airborne powderparticles already entrained in air. Therefore, the mentioning of“motion” or “moving” in relation to “powder” or “powder dose” or “dose”refers to the dose, preferably loaded on a substrate member, before thepowder particles are released and dispersed into air. Thus, the dosecomprises at least one powder deposit, e.g. in a single, concentratedspot or in a series of such spots, or a deposit or deposits spread outonto an area of the substrate member. The pattern of how a dose isarranged onto the substrate member depends mainly on the selected methodof dose filling, e.g. gravimetric, volumetric, electrostatic andelectro-dynamic methods may be used, including combinations thereof.

The relative motion between powder dose and suction tube preferablybegins, either automatically by breath-actuation or by manual control,when a pre-defined, minimum airflow has already been established throughthe suction tube. The minimum airflow develops when a pre-defined,minimum suction power is applied to the suction tube, said suction powerselected to secure enough Air-razor power to release the powder of thedose. The timing of the motion must be adapted to the style and size ofthe substrate member and the volume and mass of the dose. We have foundthat an optimum time for the motion to be completed is between 0.2 and 2seconds, but the performance of the Air-razor device is not necessarilyless at shorter motion intervals than 0.2 seconds or longer intervalsthan 2 seconds. In any particular application the formulation of thedrug powder, the dose volume and dose mass must be considered whenoptimizing the Air-razor performance. For instance, we have surprisinglyfound that compact, volumetrically metered doses in a range from below 1mg to more than 10 mg may be very efficiently released by the Air-razordevice in approximately 1 second. Such doses may be concentrated to aparticular spot on a substrate or the powder may be distributed, e.g. byshaking, over the whole substrate area without any difference inAir-razor performance. So, within the indicated time frame of 0.2 to 2seconds almost any dose is released and delivered to a user withexcellent results in emitted dose and FPD.

A satisfactory Air-razor effect is normally generated by a suctionbetween 2 and 4 kPa, which gives rise to an airflow in a range from 20l/min to 60 l/min, depending on chosen size, distance to substratemember etc. for the suction tube inlet aperture and also otherparameters play a part in the optimizing exercise. See FIG. 2 whichillustrates a timing diagram of an inhalation period ‘I’ and a suctionpressure curve ‘P’ and the following airflow ‘Q’ as a result.

FIGS. 4, 5 and 6 illustrate top and side views of different embodimentsof single deposits of doses 22 on a target area 35 of a substrate member34. As seen in the illustrations doses may be very concentrated in aspot, or spread out over most of the available area. The Air-razor ispreferably optimized with regard for the type of dose, including type offormulation, that is going to be loaded into an inhaler where theAir-razor is applied. Using a new type of blister pack, a so-called pod(patent pending), as a particular embodiment of a sealed dose container,is to be preferred in an application where the present invention is tobe put to use. See our Application U.S. Ser. No. 11/154677, which ishereby included in this document by reference. A pod container may, ifnecessary, be made as a high barrier seal container offering a very highlevel of moisture protection and which is in itself dry, i.e. it doesnot contain water. See FIG. 7 illustrating a pod carrying a sealedcontainer in a perspective drawing. FIG. 7 a shows a sealed container 33(seal 31) put into a protective casing 41 adapted for insertion into adry powder inhaler. FIG. 7 b shows a top view of the carrier/containerand indicates a dose of a dry powder medicament 22 and a dose of a drypowder excipient consisting of two depositions 21 inside the container33 under a seal 31. FIG. 7 c illustrates a side view of thecarrier/container shown in FIG. 1 b. FIG. 8 illustrates a similarcontainer to FIG. 7, but the medicament dose consists of two deposits 22and the excipient dose consists of deposit 21 after agitation of thecontainer, whereby the deposits 21 and 22 have become partly mixed in aload 23.

The medication powder comprises one or more pharmacologically activesubstances and optionally one or more excipients. As used herein theterms “powder” or “medication powder” are used to signify the substancein the form of dry powder, which is the subject of release from asubstrate member and dispersal into an airstream by the disclosedinvention and intended for deposition at a selected target area of areceiver's airways.

Short Background on the Concept of the Powder Air-Razor Method

Adhesion of Particles

Particles adjacent to other particles or to a substrate member willadhere to each other. Many different types of adhesive forces will playroles in the total adhesive force between a particle and theenvironment, whether that is another particle, an aggregate ofparticles, a substrate member or a combination thereof. The types ofadhesive forces acting on a particle can be van der Waal forces,capillary forces, electrical forces, electrostatic forces, etc. Therelative strengths and ranges of these forces vary with e.g. material,environment, size and shape of the particle. The sum of all these forcesacting on a particle is hereinafter referred to as an adhesive force.

Release and Entrainment of Particles

FIG. 1 illustrates forces acting on a particle. The force caused byairflow 303 acting on a particle 101 can be divided into two parts, dragforce 305 acting parallel to the airflow, and lift force 304 actingperpendicular to the airflow. The condition for freeing the particle isin the static case that lift and drag forces exceed adhesion 301 andfriction 302 forces.

In order to release particles from a substrate and/or from otherparticles it is not sufficient to let a force act on the particles withenough strength for release and entrainment. If a strong force acts on acluster of particles, such that more or less the same force acts on allparticles, the cluster will be entrained into the airflow withoutparticles separating. The condition for release may thus be stated as:The difference in external forces acting on two particles must overcomethe adhesion and friction forces holding them together. Attaining adifference in force from airflow may be done efficiently by creatingshear forces, and hence the Air-razor method makes use of high shearforces in the area of the powder deposited onto a substrate member.

The efficiency of the Air-razor method may be optimized by carefuldesign of the geometry of involved flow elements with the aim to reachas high a velocity as possible in the releasing area around the suctiontube inlet aperture, i.e. where the dose is to be found, but at the sametime a smooth transportation of air in other areas. This will minimisethe dissipative losses where not wanted and so preserve energy for usein the area adjacent to and into the powder deposit(s). When suction isapplied to the suction tube outlet, a low-pressure develops thataccelerates the air through the suction tube inlet aperture during ashort period before a steady state condition is reached. Initially,during the start-up period as the air picks up inertia, the velocity isnot high enough to generate the necessary shear forces. Preferably,during this initial period the air flow is allowed to build up beforethe powder dose is brought adjacent to the suction tube. This ensuresthat the conditions for an efficient release of the powder exist beforethe dose deposit(s) is (are) attacked by the air stream. The Air-razorinvention makes use of the concentrated flow close to the inside wall ofthe suction tube inlet nozzle as well as the surfaces of the substratemember, and especially the small gap between the aperture wall on thesuction tube inlet and the substrate member.

Air-Razor Movement

The importance of shear forces for an efficient release of particles andthe theoretical background as to why has been discussed in theforegoing. The relative motion introduced between the suction tube andthe load of powder, i.e. the substrate member normally serving ascarrier, is instrumental in attaining and maintaining the desiredconditions stated for releasing all of a powder dose and not just partof it.

The main advantages given by the motion are:

-   -   During an initial acceleration phase inertia builds up giving a        high velocity air flow    -   Shear forces close to a wall are spread over a large area over        time    -   Efficient use of available energy, preferably suction pressure        Inertia Build Up

The low-pressure created by the suction through the suction tube drivesair to flow in the direction of the low-pressure. Building up inertiameans accelerating the mass in a system, i.e. the mass of the airitself, hence giving the desired high velocity air flow after theacceleration period. The velocity of the flow increases to a point wherethe flow resistance makes further increase impossible, unless the levelof low-pressure is decreased, i.e. the pressure drop is increased, orthe flow resistance is decreased.

Optimizing Shear Force Spreading

The area exhibiting the highest shear forces is concentrated close tothe wall of the inlet aperture of the suction tube nozzle. Thisconcentrated area must be adapted to the powder deposit or depositsmaking up the dose and which occupy a small or large percentage of theavailable dose target area of a substrate member. Different powderformulations may behave very differently when filled as at least onedeposit on the substrate member. For instance, formulations comprisingvery porous particles may have very low bulk density and may alsopresent quite small adhesive forces. They often flow quite easily, evenif the average particle size is small, and these powders are thereforeeasy to use in conventional filling systems. Because of the smalladhesive forces between particles and between particles and substratethe deposited powder dose is easily broken up after filling, e.g.volumetrically, and the dose may spread itself over a large part of theavailable substrate area. The total volume of the dose is also ratherbig, since the powder bulk density is low, compared to the same dosemass of non-porous particles of the same substance. The dose of aformulation of porous particles, as the example shows, needs anAir-razor device, which is capable of spreading the shear forces over abig volume, but which must not necessarily present very high shearforces, since the individual particles are comparatively easy to releasefrom each other and from the substrate. In short, the Air-razor shouldbe adapted to spreading the available airflow energy over a big volumein this case. On the other hand, if the formulation comprises fine,micronized particles from e.g. a jet-mill process, the powder typicallypresents high adhesive forces, it does not flow easily, porosity is low,bulk density is high and filling is difficult using prior art methods.In this example the dose deposit or deposits hold together well on thesubstrate member after filling and the substrate area occupied by thedose is small, perhaps not more than a single deposit in the form of adot, on a fraction of the available dose target area. In such caseindividual particles require fairly high levels of supplied energy inorder to be released and entrained in the airstream. Here, therequirements on the Air-razor are quite different from the previousexample. Shear forces need to be high and more concentrated to ensurethat all particles of the dose are subjected to a sufficiently highforce to be released and de-aggregated from the cluster of particlesthey may be part of. In this example it is still most important that theshear forces are applied gradually to the dose, even though the depositor deposits are small in size. A third example is a formulationcomprising a majority of large particles, preferably of an excipientsubstance, in a mixture with small particles, some of which constitutingthe API to be delivered to the deep lung, for instance. This formulationis called an ordered mixture where the large particles act as carriersof the small particles. When a dose of the mixture is enhaled the smallparticles separate from the big ones and are transported by theinspiration air into the lungs of the user, while the big particlesimpact in the mouth or upper airways, where they have no effect. Typicalproperties of an ordered mixture are high flowability, ease of filling,e.g. volumetrically, high dose mass often necessary, fairly easy torelease dose, moderate adhesive forces. The dose deposit or depositshold together well on the substrate member after filling, but take upmuch more space than the dose of micronized particles in the precedingexample. The deposits are not difficult to break up in random clustersof particles by providing energy e.g. vibration. In the example, theAir-razor needs to cover the available dose target area and at the sametime providing fairly high shear forces over a rather big volume inorder to release all particles of the mixture.

Optimizing the Air-razor for a dose of a particular powder formulationinvolves a set of Air-razor parameters, including suction tube inletaperture size, shape, aperture distance and angle to the substrate,duration of suction and speed and time of relative motion. The relativemotion between the suction tube and the dose will let the relativelysmall and concentrated area of high shear stress traverse over the areaoccupied by the dose. The velocity of the airflow will not be affectedby the motion of the suction tube in relation to the powder dose,because the speed of the relative motion is very much lower than thevelocity of the air flow going into the suction tube inlet. However, themotion of the suction tube forcibly shifts the position of the drivinglow-pressure relative the contour of the dose in the direction of themotion. Thus, the area of high shear forces moves along a path,controlled by the relative motion of the suction tube, such that thehigh shear forces gradually disperse powder particles into air.Preferably, the path begins just outside a point of contact between thehigh shear force area of flowing air and the deposit(s) of the powderdose and passes the dose deposits, if more than one, from the beginninguntil the end on the substrate member. Thus, the gradual releasing anddispersal of a medication powder is an inherent essential characteristicof an Air-razor method.

For example, in a preferred embodiment of the optimized Air-razor methodand device, the dose is deposited by a gravimetric, volumetric orelectric method onto a substrate member of a pod container. At least apre-defined, minimum suction is applied to an outlet of a suction tubealso comprising a dose-adapted inlet aperture, thereby starting up atleast a minimum airflow into the suction tube inlet e.g. from ambientair. The pod and thereby the dose therein are then moved past the inletaperture at close proximity in an interval of preferably 0.2 to 2seconds. The dose is hereby gradually released and entrained into theairflow going through the suction tube.

In another preferred embodiment of the optimized Air-razor method anddevice, similar to the above, the suction tube inlet aperture is movedat close range past the dose in the pod container, thus releasing thedose by using the Air-razor effect in analogy with the above example.

In yet another but similar embodiment to the ones described above, thesuction tube inlet aperture and the dose both move to make the airflowinto the inlet aperture release the dose gradually by using theAir-razor effect in analogy with the above examples.

The above written description of the invention provides a manner andprocess of making and using it such that any person skilled in this artis enabled to make and use the same, this enablement being provided inparticular for the subject matter of the appended claims, which make upa part of the original description and including an improved method ofreleasing and dispersing into an airstream a dose of dry powder,releasably retained onto a substrate member, comprising:

-   -   filling a dry powder dose of a selected powder formulation onto        the substrate member, said dose intended to be delivered by an        inhaler;    -   optimizing an inlet aperture of a suction tube for said dose;    -   applying at least a pre-defined suction pressure to an outlet of        the suction tube, said suction thereby creating an airstream        through the suction tube from inlet to outlet;    -   introducing a relative motion between the suction tube and the        substrate member within a time frame of a single suction effort;    -   maintaining said suction pressure for the duration of said        motion from beginning to end, such that the inlet aperture        appears to traverse the substrate member or vice versa including        the dose thereon, whereby the motion and the airstream together        produce a powder Air-razor effect that distributes sufficient        shearing power onto the full volume of the dose by means of said        motion, said shearing power releasing the powder of the dose        from the substrate member and dispersing the powder dose into        the airstream.

Similarly fully enabled is a method of optimizing emission of a dose ofdry powder, releasably retained on a substrate member by use of anAir-razor method, comprising

-   -   filling a dose of a selected powder formulation, said dose        intended for inhalation, onto the substrate member using a        chosen method of filling;    -   adapting an inlet aperture of a suction tube to the dose and        positioning the aperture adjacent to the substrate member at a        first, selected distance from the substrate member and at a        second, chosen distance from the dose on the substrate member;    -   applying a pre-defined suction pressure to a mouthpiece in fluid        connection with an outlet of said suction tube and introducing a        relative motion between the suction tube and the substrate        member, or vice versa;    -   maintaining said suction pressure for the duration of said        motion from beginning to end, such that the inlet aperture        appears to traverse the substrate member, or vice versa, and the        dose thereon, whereby the motion and the airstream together        constitute an Air-razor effect that releases and disperses the        powder dose into the airstream going through the mouthpiece into        a receiver;    -   measuring the amount of retained powder on the substrate member        and optionally in the suction tube and/or the mouthpiece and        optionally measuring the fine particle fraction of the emitted        dose;    -   comparing measurement results with previously determined        requirements, and repeating the method, if the measurement        results are not satisfactory, using a revised set of Air-razor        parameters, including first aperture size, shape, aperture        distance to the substrate, duration of suction and speed and        time of relative motion until the results meet the requirements        or the optimization process is stopped.

Similarly fully enabled is an Air-razor device optimized according toclaim 13 for releasing a dry powder medication dose from a substratemember and disperse the dose into an airflow, wherein

the Air-razor device comprises:

-   -   a suction tube having an inlet aperture adapted to the dose and        a larger outlet aperture;    -   said inlet aperture positioned adjacent to the substrate member    -   means of moving the suction tube in relation to the substrate        member, or vice versa    -   means of controlling the speed of motion suction tube-substrate        member.

As used above, the phrases “selected from the group consisting of;”“chosen from,” and the like include mixtures of the specified materials.

All references, patents, applications, tests, standards, documents,publications, brochures, texts, articles, etc. mentioned herein areincorporated herein by reference. Where a numerical limit or range isstated, the endpoints are included. Also, all values and subrangeswithin a numerical limit or range are specifically included as ifexplicitly written out. Terms such as “contain(s)” and the like as usedherein are open terms meaning ‘including at least’ unless otherwisespecifically noted.

The above description is presented to enable a person skilled in the artto make and use the invention, and is provided in the context of aparticular application and its requirements. Various modifications tothe preferred embodiments will be readily apparent to those skilled inthe art, and the generic principles defined herein may be applied toother embodiments and applications without departing from the spirit andscope of the invention. Thus, this invention is not intended to belimited to the embodiments shown, but is to be accorded the widest scopeconsistent with the principles and features disclosed herein.

1. A method of releasing and dispersing into an airstream a dose of drypowder, releasably retained onto a substrate member, comprising:applying suction pressure to an outlet of a suction tube, said suctionthereby creating an airstream through the suction tube from inlet tooutlet; introducing a relative motion between the suction tube and asubstrate member, having a dry powder dose of a selected powderformulation thereon, within a time frame of a single suction effort, theinlet aperture of the suction tube being optimized for a release of saiddose; maintaining said suction pressure for the duration of said motionfrom beginning to end, such that the inlet aperture and the substratemember including the dose thereon traverse one another, whereby themotion and the airstream together provide sufficient shearing power ontothe full volume of the dose by means of said motion, said shearing powerreleasing the powder of the dose from the substrate member anddispersing the powder dose into the airstream by creating a differencein external forces acting on dose particles that overcomes the adhesionand friction forces holding them together.
 2. The method according toclaim 1, comprising the further step of selecting a volumetric,gravimetric, electrostatic or electro-dynamic method of filling thedose, or a combination of such methods.
 3. The method according to claim1, comprising the further step of selecting an optimal position for saidaperture adjacent to the substrate member at a first, selected distancefrom the substrate member and at a second, chosen distance from the doseon the substrate member.
 4. The method according to claim 1, comprisingthe further step of traversing the substrate member by the suction tubeinlet aperture or vice versa, at least partly, including the dosethereon, at least partly, whereby the powder of the dose is released, atleast partly, from the substrate member and dispersed at least partlyinto the airstream.
 5. The method according to claim 1, comprising thefurther step of providing, by the pre-defined suction pressure power, ashearing power adapted to the powder formulation, the dose mass and thephysical dose volume, in an area adjacent to the inlet aperture of thesuction tube, said shearing power preferably being applied to all partsof the dose gradually by means of the relative motion between thesuction tube and the substrate member, or vice versa.
 6. The methodaccording to claim 5, comprising the further step of providing a levelof shearing power that is able to release, at least partly, particlescontained in the powder dose.
 7. The method according to claim 1,comprising the further step of optimizing size and shape of the inletaperture to be adapted to the properties of the powder formulation ofthe dose, the dose mass, and the physical dose volume; arranging therelative motion of the inlet aperture to track at the selected distancethe surface curvature of the substrate member, or vice versa, where thedose is present upon at least a part of said surface.
 8. The methodaccording to claim 7, comprising the further step of applying saidAir-razor effect on a dose concentrated to a single spot on thesubstrate member, said dose filled using a method or methods accordingto claim
 2. 9. The method according to claim 7, comprising the furtherstep of applying said Air-razor effect on an extended or elongated doseon the substrate member, said dose filled using a method or methodsaccording to claim
 2. 10. The method according to claim 7, comprisingthe further step of applying said Air-razor effect on a dose comprisingmore than one deposit on the substrate member, said dose filled using amethod or methods according to claim
 2. 11. The method according toclaim 7, comprising the further step of applying said Air-razor effecton a combined dose comprising at,least one deposition each of at leasttwo different active ingredients on the substrate member, said combineddose filled using a method or methods according to claim
 2. 12. Themethod according to claim 7, comprising the further step of applyingsaid Air-razor effect on a single or a combined dose distributed atrandom on the substrate member, said dose filled using a method ormethods according to claim
 2. 13. A method of optimizing emission of adose of dry powder, releasably retained on a substrate member by use ofan Air-razor method, comprising: setting Air-razor parameters accordingto characteristics of the dose and the dry powder; applying apre-defined suction pressure to a mouthpiece in fluid connection with anoutlet of a suction tube and moving the suction tube relative thesubstrate member, or vice versa; maintaining said suction pressure forthe duration of said motion from beginning to end, such that the inletaperture and the substrate member and the dose thereon traverse oneanother, whereby the motion and the airstream together constitute anAir-razor effect that releases and disperses the powder dose into theairstream going through the mouthpiece into a receiver; measuring theamount of retained powder on the substrate member and optionally in thesuction tube and/or the mouthpiece and optionally measuring the fineparticle fraction of the emitted dose; comparing measurement resultswith previously determined requirements, and repeating the method, ifthe measurement results are not satisfactory, using a revised set ofAir-razor parameters, including first aperture size, shape, aperturedistance to the substrate, duration of suction and speed and time ofrelative motion, until the results meet the requirements or theoptimization process is stopped.
 14. The method according to claim 13,comprising the further step of selecting a volumetric, gravimetric,electrostatic or electro-dynamic method of filling the dose, or acombination of such methods.
 15. The method according to claim 13,comprising the further step of applying said Air-razor method on a doseconcentrated to a spot on the substrate member, said dose filled using amethod or methods according to claim
 14. 16. The method according toclaim 13, comprising the further step of applying said Air-razor methodon an extended or elongated dose on the substrate member, said dosefilled using a method or methods according to claim
 14. 17. The methodaccording to claim 13, comprising the further step of applying saidAir-razor method on a dose comprising more than one deposit on thesubstrate member, said dose filled using a method or methods accordingto claim
 14. 18. The method according to claim 13, comprising thefurther step of applying said Air-razor method on a combined dosecomprising at least one deposition each of at least two different activeingredients on the substrate member, said dose filled using a method ormethods according to claim
 14. 19. The method according to claim 13,comprising the further step of applying said Air-razor method on asingle or a combined dose distributed at random on the substrate member,said dose filled using a method or methods according to claim
 14. 20.The method according to claim 13, comprising the further step ofselecting the pre-defined suction pressure to be within a range from 2to 4 kPa for the duration of said motion from beginning to end.
 21. Themethod according to claim 1, comprising the further step of selectingthe duration of said motion to be at least 0.2 s and less than 2 s frombeginning to end.
 22. An optimized Air-razor device for releasing a drypowder medication dose from a substrate member and disperse the doseinto an airflow, comprising: a suction tube having an inlet apertureadapted to the dose and a larger outlet aperture; said inlet aperturepositioned adjacent to the substrate member the suction tube and thesubstrate member being moveable in relation to one another; said devicecomprising a controller for controlling the speed of motion suctiontube-substrate member in relation to one another upon movement, saiddevice being optimized by setting Air-razor parameters according tocharacteristics of the dose and the dry powder; applying a pre-definedsuction pressure to a mouthpiece in fluid connection with an outlet of asuction tube and moving the suction tube relative the substrate member,or vice versa; maintaining said suction pressure for the duration ofsaid motion from beginning to end, such that the inlet aperture and thesubstrate member and the dose thereon traverse one another, whereby themotion and the airstream together constitute an Air-razor effect thatreleases and disperses the powder dose into the airstream going throughthe mouthpiece into a receiver; measuring the amount of retained powderon the substrate member and optionally in the suction tube and/or themouthpiece and optionally measuring the fine particle fraction of theemitted dose; comparing measurement results with previously determinedrequirements, and repeating the method, if the measurement results arenot satisfactory, using a revised set of Air-razor parameters, includingfirst aperture size, shape, aperture distance to the substrate, durationof suction and speed and time of relative motion, until the results meetthe requirements or the optimization process is stopped.
 23. A drypowder inhaler device, wherein the inhaler device comprises an optimizedAir-razor device according to claim 22.